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In 1956, Harman proposed the Free Radical Theory of Aging, postulating that free radical reactions are involved in the changes associated with disease and aging processes (Harman, 1956). Of the many existing theories for aging, this one remains the most rational and credible. Later, Harman suggested that mitochondria might be the biological clock in aging since the rate of oxygen consumption should determine the rate of accumulation of mitochondrial damage produced by free radical reactions (Harman, 1972).

Today, with subsequent contributions and refinements from several scientists, the Free Radical Theory of Aging has evolved into the Mitochondrial Theory of Aging. Very recently, in an elegant experimental study, my long-time collaborator Gjumrakch Aliev and collaborators (2008) corroborated this theory. By using qualitative and quantitative electron microscopy techniques, the authors analyzed the neuronal mitochondrial ultrastructural changes of young and old rats with or without supplementation of the mitochondrial metabolites, acetyl-L-carnitine and R-α-lipoic acid. The authors observed that the hippocampus of control animals shows an age-dependent decrease in the number of intact mitochondria and an increase in mitochondria with broken cristae, these alterations being more evident in vascular endothelial cells (Aliev et al., 2008).

These results clearly support previous studies showing that mitochondrial decay plays a key role in aging and age-associated neurodegenerative diseases such as Alzheimer disease (Shigenaga et al., 1997; Hagen et al., 1997; Hirai et al., 2001; Aliev et al. 2004; Moreira et al., 2007a). However, a clear improvement of mitochondrial ultrastructure was observed in young and aged rats supplemented with acetyl-L-carnitine and R-α-lipoic acid (Aliev et al., 2008). The authors observed that these mitochondrial metabolites are capable of increasing the proliferation of intact mitochondria and reducing the number of severely damaged mitochondria. These results support previous studies indicating that delaying brain mitochondrial decline with mitochondrial metabolites and antioxidants could be a promising weapon in the fight against aging and age-related diseases (Hagen et al., 2002; Liu et al., 2002; Moreira et al., 2007b).

However, a majority of available antioxidants have not proven to be particularly effective against many of these disorders. A possibility for this “inefficacy” is that some of these compounds do not reach the relevant sites of free radical generation, especially if mitochondria are the primary source of reactive oxygen species. So, the increase in mitochondrial biogenesis and the protection of mitochondrial viability with compounds that directly target mitochondria, such as acetyl-L-carnitine and R-α-lipoic acid, can minimize further reactive oxygen species generation, thus breaking the vicious cycle among mitochondrial dysfunction, reactive oxygen species production, and cell degeneration and death. Due to their low toxicity, low cost, and their ability to target the earliest sources of oxidative stress, therapies based on mitochondrial metabolites are particularly attractive to delay/arrest aging and age-related diseases.

The authors treated young and old rats with lipoic acid + acetylcarnitine oral supplementation. They performed a careful EM analysis of hippocampi from the mice. They emphasized quantitative and ultrastructural mitochondrial analyses. As the mice aged, the number of intact hippocampal mitochondria decreased and the number of damaged mitochondria increased. LA and ALCAR supplementation helped preserve the number of intact mitochondria and overall mitochondrial ultrastructure in the aged rats. It is concluded ALCAR + LA may ameliorate age-related mitochondrial pathology and thereby ameliorate evolution of the aging phenotype.

While previous work from this group has shown ALCAR and LA supplementation benefit aging rats, this is the first paper to provide a detailed ultrastructural analysis of mitochondria from the treated rats. The reported data are provocative from a translational perspective. This study also sheds some light on the issue of whether overall rates of mitochondrial biogenesis change with aging.